1. Field of the Invention
The invention relates to a method for the imaging of meningiomas using phenylbenzothiazole derivatives or stilbene derivatives or biphenylalkyne derivatives, and using a medical imaging technique such as positron emission tomography imaging.
2. Description of the Related Art
Meningiomas are the second most common tumor inside the skull with an incidence of approximately six per 100,000, and meningiomas account for 13-26 percent of all primary intracranial tumors. Approximately 90% of meningiomas are benign, with the rest being more aggressive, or even malignant. The benign classifications include meningothelial meningioma, fibrous/fibroblastic meningioma, transitional (mixed) meningioma, psarnrnomatous meningioma, angiomatous meningioma, microcystic meningioma, secretory meningioma, lymphoplasmacyte-rich meningioma and metaplastic meningioma. The more aggressive classifications of meningiomas include, atypical meningioma, clear cell meningioma, chordoid meningioma, rhabdoid meningioma, papillary meningioma and anaplastic (malignant) meningioma.
Most often standard imaging leads to a confident diagnosis of benign meningioma. However, the variability of types of meningiomas corresponds with the wide range of possible appearances on standard imaging. In addition, many other types of tumors can arise in the membranes overlying the brain where meningiomas most commonly arise; pia, arachnoid and dura matter. These two factors can lead to a lack of diagnostic confidence with conventional diagnostic imaging. This lack of confidence can have dramatic and negative effects on a patient's medical care.
The majority of meningiomas can be confidently diagnosed based on conventional imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI). When a mass in the dura is identified in a patient based on CT or MRI, the most likely diagnosis is meningioma. A minority of meningiomas contain calcifications, and most meningiomas have higher density then the surrounding brain. These findings are best evaluated by CT, and both increase confidence in the diagnosis of meningioma. Diagnostic confidence is also increased when a dural based mass has a “dural tail sign”, or when it uniformly enhances with intravenous gadolinium. These findings are best evaluated on MRI. Stability or very slow growth of the mass over many months to years also increases confidence in the diagnosis of meningioma. With these criteria the majority of meningiomas located in the dura can be diagnosed with confidence, either at their initial identification on CT and MRI, or in time when they prove to be stable in size.
Beyond CT and MRI there are other adjunct methods currently used to help diagnose meningiomas. Angiography has historically been used to suggest the diagnosis of meningioma. Demonstration of arterial supply from meningeal vessels and delayed vascular blush on angiography are characteristic of meningiomas. However, these findings are neither sensitive nor specific, therefore CT and MRI have proven more useful than angiography for the diagnosis of meningiomas. Angiography is currently reserved for embolization of meningiomas as a primary therapy, or to reduce the risk of intraoperative hemorrhage. Surgery results in diagnosis/treatment of meningiomas, but reported surgical mortality rate is as high as 14.3%. Lumbar puncture with cerebrospinal fluid (CSF) testing is not useful for diagnosing meningiomas. However, CSF testing is potentially helpful for diagnosing metastatic disease. Leptomeningeal invasion can give rise to tumor cell dissemination in the CSF, which can be detected by lumbar puncture with cytology, however this is often falsely negative. There are no good laboratory tests available for the diagnosis of meningioma. Meningiomas are most often diagnosed incidentally with imaging. Physical exam and clinical history are often normal in patients with meningiomas. When there are signs and symptoms related to a meningioma, they are most often non-specific, related to the mass effect of the meningioma.
Thus, there are problems with the current methods for diagnosing meningiomas. A minority of meningiomas can not be diagnosed with confidence based current imaging methods. Meningiomas can look like other tumors. Meningiomas can occur in locations where other tumors are common. Meningiomas can occur elsewhere in the body outside of the dura. Although meningiomas are more common, many less common tumors can mimic the appearance of a meningioma. Therefore, the diagnosis of meningioma can not always be made with confidence based on CT and MRI alone, and sometimes when the diagnosis of meningioma is felt to be confident, it is incorrect. This is particularly important in cases where the different diagnoses being considered require very different therapy, or the real diagnosis is not even considered, such as with metastatic malignancy.
In patients with meningiomas that have an atypical imaging appearance, the differential diagnosis based on CT and MRI is often broader, less confident and includes metastatic disease. Meningiomas can have widely varied appearances on CT and MRI, such as cystic changes, adjacent reactive bony proliferation, and adjacent reactive brain parenchyma edema. Examples of meningiomas mistaken for other tumors are plentiful. Misdiagnoses include: orbital metastatic carcinoma; carcinoid tumor; intramedullary spinal tumor; calvarial metastasis; schwannoma; idiopathic hypertrophic pachymeningitis, pituitary adenoma and glial or metastatic tumors.
In some patients, tumors are identified within the dura in locations where other known common tumors can occur. For example, in the cerebropontine angle, the differential diagnosis for a tumor commonly includes schwannoma and meningioma, and less likely metastasis, melanoma, sarcoidosis, tuberculosis, Erdheim-Chester, lymphoma, paraganglioma, chordoma. In the region of the sella turcica, the differential diagnosis for a tumor commonly includes pituitary adenoma and meningioma, and less likely craniopharyngioma, glioma, gerrninoma, hamartoma, aneurysm, trigeminal schwannoma, pituitary carcinoma, chordoma, metastasis and infection. Meningiomas can occasionally occur outside of the cranial vault and outside of the dura, making their correct diagnosis in these locations much more difficult. When tumors associated with the dura are found in the spine, the differential commonly includes meningioma, schwannoma, neurofibroma and metastasis. Meningiomas can occur outside the dura in the cervical spine. Other less common extradural locations where meningiomas have been found include the mediastinum, the ventricle of the brain, lungs, mandible and bone. Rarely meningiomas can even metastasize from the dura to distant locations, such as to the lungs.
Numerous articles have demonstrated that although most dural tumors can be confidently diagnosed as meningiomas based on CT and MRI, uncommonly many other tumors can mimic the appearance of a meningioma. Therefore, the differential for dural based masses that look like meningiomas on CT and MRI is very broad. The general categories for etiologies of these meningioma-like dural masses include metastatic disease, lymphoma, multiple myeloma/plasmacytoma, primary dural tumors, infections, inflammatory tumors, and other systemic diseases.
The differentiation between meningioma and dural metastasis in particular can be very difficult based on current imaging methods. This differentiation is critical, as often dural metastasis require far more aggressive medical and surgical management than meningiomas. Since meningiomas are common, even in patients with a known metastatic malignancy, the possibility remains that a dural based mass represents a coincidental meningioma. Dural metastases are found at autopsy in 8-9% of patients with advanced systemic cancer. Prostate, breast, lung and stomach cancer are the most common malignancies metastasizing to the dura. However, renal, bladder, thyroid, colon, rectal, pancreatic, gallbladder, hepatobiliary, cervical, endometrial, choriocarcinoma, mesothelioma, neuroblastoma, sarcoma, seminoma, and other adenocarcinomas have also been reported to metastasize to the dura. The diagnosis can be further confused since, the patient's primary malignancy may be unknown and/or the dural metastasis may be the initial presentation of systemic malignancy. Furthermore, metastasis to the dura can occur long after the patient has been in complete remission.
There have been advances in imaging for the diagnosis of meningioma. Imaging modalities continue to advance and new techniques in MRI and molecular imaging, may prove helpful with the differentiation between meningioma and other tumors such as metastasis. The most promising modalities are Dynamic contrast MRI with cerebral blood volume mapping and octreotide-analogue based positron emission tomography/computed tomography (PET/CT). Diffusion tensor MRI may help to tell benign from aggressive meningiomas, based on one small preliminary study. However, diffusion tensor MRI has not been shown to differentiate meningiomas form other types of tumors, such as metastasis.
Dynamic contrast MRI with cerebral blood volume mapping has shown some promise in helping to differentiate meningiomas from metastasis in at least two small studies. With this technique intravenous contrast enhanced MRI is used to generate cerebral blood volume maps of the brain and surrounding tissues. These maps are used to measure the relative cerebral blood volume of the tumor compared to brain tissue as an internal control. These small preliminary studies suggest that the relative cerebral blood volume of meningiomas tends to be higher then the relative cerebral blood volume of metastatic tumors. This method is unproven, but shows promise for differentiating meningiomas from metastasis. It is as yet unclear if dynamic contrast MRI techniques will be helpful for differentiating meningiomas from other types of tumors. In addition, intravenous MRI contrast agents are required to perform these studies, therefore patients with renal failure are not able to undergo these exams. This is because, patients with renal failure are at risk to develop nephrogenic systemic fibrosis if they receive gadolinium containing intravenous MRI contrast agents. Nephrogenic systemic fibrosis is a serious condition involving fibrosis of skin, joints, eyes, and internal organs, that has been linked to the use of at least 4 of the 5 intravenous MRI contrast agents currently approved by the U.S. Food and Drug Administration; Omniscan, Multihance, Magnevist, and OptiMARK.
Fluorodeoxyglucose (FDG)-PET or FDG-PET/CT can be used in the imaging of dural tumors. The standard uptake value (SUV) of FDG seen within a meningioma has been shown to be somewhat predictive of how aggressive a meningioma is, and how likely the meningioma will be to recur if surgically removed. Meningiomas that do take up significant FDG are usually atypical or even malignant. However, since meningiomas and the other tumors that are seen in the same locations can have variable FDG uptake on FDG-PET/CT, there is limited use of FDG-PET/CT for the diagnosis of meningioma. For example, often the differential for a tumor based on CT and MRI includes meningioma versus other tumors, such as a schwannoma, that both have little or no FDG uptake. Thus FDG-PET/CT is only of limited help in the diagnosis of meningioma in these situations. For other tumors, the differential based on CT and MRI includes aggressive meningioma versus other tumors, such as metastasis, that both have moderate to high FDG uptake. Again, in this situation FDG-PET/CT is of limited value. When the differential includes benign meningioma versus metastasis, FDG-PET/CT can be helpful. In this case, if the tumor in question has low or no FDG uptake, then the diagnosis of metastasis is less likely and meningioma more likely. However, even in this situation other tumors that do not take up FDG remain on the differential. Perhaps due to the above reasons, there are no studies to date that show FDG-PET/CT can help differentiate meningiomas from dural metastasis.
FDG is the only PET tracer currently approved by the U.S. Food and Drug Administration for tumor imaging. However, many experimental PET tracers are available. PET/CT performed with some of these experimental tracers may prove helpful in the diagnosis of meningiomas, but most are nonspecific. C11-methionine is taken up by some meningiomas. C11-methionine is taken-up in a nonspecific manner, thought to be due in large part to cellular protein production. Therefore C11-methionine is increased in many actively growing tumors. C11-methionine, similar to FDG, would likely not be taken-up by the majority of meningiomas, which are not fast growing. C11-methionine would not likely be useful for differentiating between aggressive meningiomas and dural metastasis, since both would likely have an increased SUV. 2-F-18-fluoro-L-tyrosine is taken up by some meningiomas. 2-F-18-fluoro-L-tyrosine is taken up in a non-specific manner by cells undergoing DNA synthesis, such as cells that are multiplying. Therefore, 2-F-18-fluoro-L-tyrosine has similar benefits and limitations to C11-methionine with regard to imaging of meningiomas. 16 alpha[F-18]fluoro-17 beta-oestradiol (F 18-FES) binds to estrogen receptors and is taken up by some, but not all meningiomas in one small preliminary study. Therefore, F18-FES-PET/CT may not prove to be highly sensitive for meningiomas. In addition, F18-FES binds to other tumors that express estrogen receptors, such as endometrial cancer, potentially making F18-FES nonspecific for meningiomas.
Radioactive tracers that emit single photons are used in planar nuclear imaging and single photon emission computed tomography (SPECT), and can be used in imaging of meningiomas. Many single photon tracers are approved for medical imaging use by the U.S. Food and Drug Administration. However, like most PET tracers, most single photon emitting tracers are nonspecific for meningiomas. For example, Thallium-201 SPECT imaging is somewhat useful for predicting histological types of meningiomas, but is nonspecific and is not useful for diagnosing meningiomas.
Meningiomas have been shown to express somatostatin 2 receptors and can therefore be imaged by octreotide (brand name Sandostatin, Novartis Pharmaceuticals, CAS#83 150-76-9, ATC code HO1CB02) and other somatostatin analogues. Octreotide is most commonly used for imaging of neuroendocrine tumors and can be used in SPECT or PET imaging. Octreotide can be linked to (111)Indium, which is a single photon emitter used in planar and SPECT imaging, or can be linked to 68Gallium, which is a positron emitter used in PET or PET/CT imaging. (111)indium-octreotide is a well studied tracer that binds somatostatin receptors, and is taken up by meningiomas. (111)Indium-Octreotide is approved for imaging by the U.S. Food and Drug Administration, whereas 68Ga-DOTATOC and 68Ga-DOTANOC are currently experimental labeled octreotide analogues. 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraaceticacid (DOTA) is used to link 68Ga to one of at least 2 octreotide analogues, 1-Nal3-octreotide (NOC) or D Phe1-Tyr3-octreotide (TOC), thus they are called 68Ga-DOTANOC or 68Ga-DOTATOC. More is currently published on 68Ga-DOTATOC. In one study, 68Ga-DOTANOC-PET/CT may result in less radiation to patients than 68Ga-DOTATOC-PET/CT.
Octreotide appears to have good sensitivity for meningiomas, but is not perfect. Despite close to 100% of meningiomas reported to express somatostatin receptors, specifically receptor 2, sensitivity by imaging is lower. Some of the false negative studies may be due to small volume of some tumors. However, another theory is that an intact blood brain barrier may prevent octreotide from labeling some meningiomas. SPECT imaging, even when combined with CT, lacks the resolution of PET imaging and is generally considered inferior as a modality. (68)Gallium-DOTATOC-PET/CT shows better resolution. (68)Gallium-DOTATOC-PET/CT also shows a high signal to background ratio in meningiomas, since the normal brain does not take up octreotide. Octreotide tracers shows strongest uptake in neuroendocrine tumors, neuroectodermal tumors, renal cell carcinoma, small cell lung cancer, breast cancer, prostate cancer and malignant lymphoma. In addition to meningioma, (68)Gallium-DOTATOC is taken up by other tumors that may be on the differential for a dural mass, like some forms of metastatic disease, lymphoma, pituitary adenomas, and glial tumors. Octreotide imaging studies may have uses related to meningiomas beyond initial diagnosis. Octreotide imaging may prove helpful in follow-up post surgery for recurrent/residual meningioma, as MRI can be confusing due to postoperative changes. (68)Gallium-DOTATOC-PET/CT has been proposed as a good modality for the planning of focused forms of radiation therapy, such as fractionated stereotactic radiotherapy, and may see tumor extensions into the dense skull base better than other modalities.
Octreotide studies are time consuming to perform. (111)Indium-octreotide planar and SPECT imaging is routinely done at 24 hours, but 4 hours may be sufficient, detecting most meningiomas greater that 5 ml in volume. However, even 4 hours is a long wait when compared to the more conventional MRI and CT imaging, and is disruptive to patient's schedules. With (68)Gallium-DOTATOC-PET/CT, the scan is routinely performed 120 minutes after injection, with peak/plateau activity occurring somewhere between 60 and 120 minutes.
Thus, patients who have a history of cancer and find a new tumor in the meningeal membranes that envelope the brain are faced with a common diagnostic dilemma. Meningiomas are the most common benign intracranial tumors, detected on MRI in 0.9% of normal adults over the age of 45. Approximately 4% of individuals diagnosed with meningiomas have a history of cancer. In addition, the incidence of meningeal metastases in patients with late stage cancer is 9-10%. Approximately 1 out of 5 patients with meningeal metastases have limited or otherwise controlled cancer at the time of diagnosis. Therefore if the meningeal tumor represents a metastasis it could greatly alter the cancer stage, prognosis and plan of care.
CT and MRI are clearly inadequate for confident distinction of meningioma from meningeal metastasis in a single imaging evaluation. The diagnosis of meningioma is suggested when a tumor is detected in the meningeal membranes that envelope the central nervous system. Typical meningiomas enhance uniformly and have an enhancing dural tail (dural tail sign) extending along the meninges. However, meningiomas have a wide variety of appearances, and only 60% have this typical appearance. The dural tail sign can be seen with many other tumors, including metastases. In fact, approximately 44% of dural metastases have a dural tail according to a recent study from Memorial Sloan-Kettering Cancer Center, and can exactly mimic typical meningiomas on imaging. The insufficient specificity of MRI is exemplified in a blinded review of imaging from patients who had surgical resection of meningeal tumors at the Cleveland Clinic. In this selected population, the diagnosis of meningioma on MRI was only 50% specific and metastatic cancer was the most common mimic. Malignancy can be excluded with multiple follow-up MRI or CT scans over 1 to 2 years if they show stability, or very slow growth. Surgical biopsy is the only quick and reliable option available to definitively differentiate meningiomas from other tumors.
Therapy for meningiomas and metastases differs greatly, and therefore improvements in diagnosis would result in clinical benefit. Greater than 97% of meningiomas are World Health Organization grade I or II, and are considered nonmalignant. When a history of cancer is not clouding the diagnosis, most meningiomas can be monitored clinically and with imaging. A small subset of meningiomas cause symptoms due to mass effect, and therefore surgery or radiation may be required. Chemotherapy is not currently useful for treating meningiomas. These treatments are in stark contrast to the more aggressive, multimodality and systemic therapies that benefit patients with meningeal metastases. Unfortunately, because of inadequate diagnostic confidence with current imaging, many patients with probable meningiomas are compelled to have surgery primarily to confirm the diagnosis and only secondarily for the purpose of treating the tumor. Surgical mortality rates are as high as 7% and significant and permanent morbidity rates are as high as 40%, depending on location of the tumor.
From the foregoing, it can be appreciated that there is a need for alternative methods for detecting or ruling out a meningioma in a patient.